The present invention relates to a method for controlling the process of manufacturing a coating of a pharmaceutical product, such as a pellet, a tablet or a capsule.
Generally, a coating of a pharmaceutical product consists of one or more films and each film consists of one or more layers. Below, xe2x80x9ccoatingxe2x80x9d is used as a comprehensive expression encompassing everything from an individual layer to a combination of several different films. Each film is the result of a single coating step, generally performed in a coating vessel, where for instance layers of the film are built up. The coating process takes place either in a fluidized bed wherein nuclei are sprayed with a specific coating mixture or by passing the nuclei through a spray dust of said mixture. Several other generally used coating techniques are known in the prior art, such as melting, aggregation etc. The total process of manufacturing a complete coating may involve a plurality of such coating steps. However, the process may as well be sequential, whereby the whole process represents a continuous flow.
Pharmaceutical products are coated for several reasons. A protective coating normally protects the active ingredients from possible negative influences from the environment, such as for example light and moisture but also temperature and vibrations. By applying such a coating the active substance is protected during storage and transport. A coating could also be applied to make the product easier to swallow, to provide it with a pleasant taste or for identification of the product. Further, coatings are applied which perform a pharmaceutical function such as conferring enteric and/or controlled release. The purpose of a functional coating is to provide a pharmaceutical preparation or formulation with desired properties to enable the transport of the active pharmaceutical substance through the digestive system to the region where it is to be released and/or absorbed. A desired concentration profile over time of the active substance in the body may be obtained by such a controlled course of release. An enteric coating is used to protect the product from disintegration in the acid environment of the stomach. Moreover, it is important that the desired functionalities are constant over time, i.e. during storage. By controlling the quality of the coating, the desired functionalities of the final product may also be controlled.
There are strict requirements from the different Registration Authorities on pharmaceutical products. These requirements will put high demands on the quality of the coating and require that the complex properties of the coating will be kept within narrow limits. In order to meet these demands, there is a need for accurate control of the coating process. Further, to be able to control the coating process; the quality of the coating should be measured directly.
The quality of the coating depends on several parameters related to physical and/or chemical properties of the coating. These principal parameters can be any of the following: chemical composition, local inhomogeneities, physical and chemical homogenity, density, mechanical properties, static parameters, modulus, tensile strength, elongation at break, compression, ductility, viscoelastic parameters, morphology, macro- and microscopic properties, amorphous and/or crystallinity, permeability, porosity, aggregation, wettability, degree of coalescence/maturity, stability and ability to resist chemical and/or physical degradation. In addition to the parameters listed above there are also other parameters not listed here. The quality of the coating affects to a great extent the release properties and has a significant impact on the storage stability. In order to keep the quality of the coating within the desired narrow limits, it is necessary to control the manufacturing process of the coating accurately.
In order to enable this accurate control, it is desired to continuously and directly evaluate the quality of the coating throughout the coating process. The present invention provides for an accurate control of a coating process for manufacturing a coating of a pharmaceutical product, which fulfills the requirements of the quality of the coating.
In a prior art method for controlling the process of manufacturing a coating, the quality of the coating is evaluated indirectly, i.e. through the release properties and the storage stability of the product. The release properties are determined by taking product samples and subjecting the samples to an environment simulating the digestive system of a human body. The amount of released active substance versus time is then measured. In order to evaluate the storage stability, the product is stored for a predetermined period of time under either established normal or accelerated conditions, whereafter, a measurement is performed on the product. An accelerated condition is typically characterized by high to temperature (30-100xc2x0 C.) and/or high humidity. If the results are unsatisfactory, the coating process is analysed, leading to adjustments of the raw materials or of the relation between components of the mixture used for the coating. Other adjustments of the manufacturing process could also be a consequence of this evaluation process. These measurements and adjustments are repeated on subsequently manufactured products, until the measured release properties and/or storage stability properties are in accordance with the desired properties.
The above described prior art method for controlling the quality of the coating is slow, i.e. the time period lapsed from the manufacture of the product until it is determined whether the product is usable or not is long. Moreover, the process of starting up a new manufacturing line, the scaling up of an existing manufacturing process, manifolding an existing manufacturing line, etc., gives a prolonged adjustment phase before a production line could be run continuously producing an appropriate coating with acceptable properties. Further, these known methods to measure the quality of the coating are indirect and rough.
A main factor commonly adjusted in order to correct the release properties is the thickness of the coating. In order to determine the thickness of the coating, the product is weighed before and after the actual coating process and the difference is determined. The difference of weight provides a rough measurement value of the thickness of the coating. This measurement value is merely a mean value of the coating thickness of an entire batch and is not fully reliable to use as a base for adjusting a manufacturing quality, i.e. the quality of the process itself but also the quality of the final product. The indirect measurements cause an additional problem. Quality variations acting disadvantageously on the product properties during storage may not be detected by means of the prior art release profile measurement. Consequently, the deteriorated release properties are not detected until after having stored the products. This causes an extremely long adjustment phase. Thus, there is also a need for a faster way to determine the storage stability of the product, in order to be able to significantly shorten the adjustment phase.
Hence, there is a great demand for improved techniques for measuring and controlling the quality of the coating in a process for manufacturing a pharmaceutical product.
The object of the present invention is to provide a method for controlling the process of manufacturing a coating of a pharmaceutical product, which method overcomes the above mentioned drawbacks of prior art, and significantly reduces the time for said adjustment phase.
The object is achieved by a method for controlling the process of manufacturing a coating of a pharmaceutical product, in accordance with the present invention. The method set out in claim 1 comprises the steps of:
performing a spectrometric measurement on said coating;
generating a sample vector of measurement values from said spectrometric measurement;
condensing said measurement values into at least one principal parameter,
comparing said at least one principal parameter to a predetermined corresponding model parameter;
determining deviations of said at least one principal parameter from said corresponding model parameter and extracting information directly related to the quality of said coating; and
controlling the process on the basis, at least partly, of said information.
The steps of performing a spectrometric measurement on the coating, generating a sample vector of measurement values and condensing said measurement values provide information directly related to the physical and/or chemical properties of the coating. These properties constitute to a great extent the quality of the coating. Thus, in accordance with this method, the quality of the coating is measured directly and the control of the manufacturing process is based, at least partly, on that measurement.
The method according to the present invention advantageously enables the control to be based on measurements of the quality of the coating of samples at any stage of the coating process. The measurements can be performed during the actual coating process, e.g. within a coating vessel or by taking out a sample from the coating vessel without interrupting or interfering with the coating process. The measurement can also be performed after the coating process, e.g. on a sample taken out of a coating vessel or on a final product.
Since the inventive employment of spectrometric measurements advantageously enables the quality of the coating analysis to be carried out in-line, i.e. in the process vessel during the manufacturing process, the present invention provides for in-line adjustments of the process. The possibility to perform in-line adjustments reduces the waste of products having properties beyond the predetermined limits.
Further objects and advantages of the present invention will become apparent from the appended claims, by the following detailed description and by means of exemplary embodiments.